2-(alkoxy or aryloxy carbonyl)-4-methyl-6-(2,6,6-trimethylcyclohex-1-enyl)hex-2-enoic acid compounds, its preparation and use

ABSTRACT

Compounds of the formula 1 
                         
wherein, R is hydrogen, alkyl or substituted alkyl, aryl or substituted aryl, are useful intermediates in the synthesis of fragrance ingredients such as Ambrox 2

The present application is a continuation of co-pending U.S. Ser. No.14/854,705, filed Sep. 15, 2015, which is a divisional application ofU.S. Ser. No. 14/563,312, filed Dec. 8, 2014, now U.S. Pat. No.9,163,000, which is a divisional application of U.S. Ser. No.13/995,368, having a 35 USC 371 (c) date of Nov. 27, 2013, now U.S. Pat.No. 8,933,253, which is a national stage application of InternationalApplication No. PCT/EP2011/73550, filed Dec. 21, 2011, which claims thebenefit of Great Britain Application No. 1021584.6, filed Dec. 21, 2010,which applications are incorporated herein by reference.

The invention is concerned with organic compounds their preparation anduse as intermediates in the synthesis of fragrance ingredients.

Many fragrance ingredients that are used by perfumers in the creation ofnew and exciting fragrance accords are commodity ingredients, that is,they are non-proprietary and versions of the ingredients, which maydiffer in price and quality, and are available from many differentsuppliers. The uptake of a particular version of such ingredients byperfumers may be based on considerations of costs as well as onperformance.

3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]furan 2, from whichcertain isomers or isomer mixtures are on the market, for exampleAmbrofix® (Givaudan), Ambroxan® (Kao), Cetalox® and Fixambrene® (bothFirmenich) is an example of such a commodity fragrance ingredient.

There remains a need to provide novel key intermediates and novelsyntheses that enable key fragrance ingredients to be produced in highpurity, good yield and in a cost-effective manner.

The invention provides in a first aspect a compound of formula 1

wherein, R is hydrogen, alkyl or substituted alkyl, aryl or substitutedaryl, more particularly R is hydrogen, methyl or ethyl.

The double bond in the side chain of compound 1 may be in theα,β-position (conjugated), or in the β,γ-position (unconjugated).

The applicant has found that compounds 1 are useful syntheticintermediates of fragrance ingredients such as3a,6,6,9a-tetramethyldodecahydro-naphtho[2,1-b]furan 2, from whichcertain isomers or isomer mixtures are on the market, for exampleAmbrofix® (Givaudan), Ambroxan® (Kao), Cetalox® and Fixambrene® (bothFirmenich).

Syntheses of compound 2 are well known in the art. The transformation ofconjugated malonates 3 (R=alkyl) to E configurated β,γ-unsaturatedesters 4 is described in WO 2007096791 (Firmenich). Therein, saidtransformation is claimed to be catalyzed by salts of the formula MX_(n)(with M being a metal of groups I, II and III, and X an anion of an acidHX) in stoichiometric amounts of an organic acid, as shown in the schemebelow. The esters 4 are key intermediates in the synthesis of theimportant fragrance compound 2.

However, α,β-unsaturated malonic acids, of which the compounds offormula 1 are examples, are generally considered as being less stableand more difficult to handle than the corresponding α, β-unsaturatedmalonates 3, e.g. during preparation, distillation, and/or under aqueouswork-up conditions, which can make their preparation as well as furthertransformation to useful compounds troublesome. This might explain whythe condensation of aldehyde 5 (see below for structure) with malonicacid has only produced acid 6 (for structure, see below) with poor E/Z(1:1) and α,β/β,γ ratios, (G. Lucius, Angew. Chem. 68, 247, 1956 or R.L. Snowdon, Siegfried Symposium, Universität Zürich, 2006).

Progress in this field has been recently reported by Breit et al. (Chem.Eur. J. 16, 3423, 2010). However, the unsaturated malonic acids producedby his method lack the γ-substituent, which would give, afterdecarboxylation, E/Z isomers in case of β,γ-unsaturation (apart from amuch different α,β/β,γ-selectivity). Futhermore, this so-called“decarboxylative Knoevenagel reaction” needs stoichiometric amounts ofnitrogen-containing bases (especially when unsaturated acids areaddressed). This makes the process uneconomic on a larger scale, aslarge quantities of the (often expensive) N-containing bases (such aspyridine, DMAP, Lutidine or DBU) have to be recovered from thewaste-waters.

Therefore, the findings that compound 1 is a useful intermediate for thepreparation of valuable fragrance ingredients, and that it can beprepared economically is surprising.

Accordingly, the invention provides in another of its aspects the use ofa compound of the formula 1 in the preparation of an ester 4 or the acid6, by the decarboxylation of the compound of formula 1.

Starting from the compounds 1, the esters 4 can be prepared, whichexhibit good β,γ/α,β and E/Z ratios, for example around 80:20 or higher,employing reagent systems used for the E-selective transformation ofmalonates 3 to esters 4 as described above. The good β,γ/α,β and E/Zratios may be attributable to the free carboxylic acid group incompounds 1, which makes the overall reaction easier to achieve, becausea transesterification step, required in WO 2007096791, is not necessary.

In a particular embodiment of the invention, decarboxylation of compound1, is carried out at ambient temperature, which may be about 0 to 130degrees, e.g. at 25° C. for the purpose of this invention. The reactionmay be carried out in a solvent, or in a solvent-free system. Ifsolvents are to be employed, it is preferred that they are polar aproticsolvents, for example DMF, N-alkyl-pyrrolidinones or dialkylsulfoxidesmore particularly DMSO. The reaction may proceed stereospecifically andwithout erosion of the E/Z ratio.

An example of this decarboxylation reaction is shown in the reactionscheme below wherein the compound 1a is decarboxylated in DMSO atambient temperature, giving the corresponding methyl ester 4a. The ester4a can be produced in this way stereospecifically and without erosion ofthe E/Z 72:28 ratio.

In another particular embodiment of the decarboxylation of compounds ofthe formula 1, the reaction proceeds thermally, e.g. between 50 and 350°C. under flow conditions, e.g. on a Gas Chromatography (GC) column. GCuses a gaseous flow but other flow conditions are contemplated, e.g. thecontinuous decarboxylation of a compound of the formula 1 dissolved in asolvent or solvent-free in a coil reactor. Appropriate flow reactors areknown to the chemist experienced in flow and analytical techniques (seefor example Ley, S. V.; Baxendale, I. R. “New Tools for Molecule Makers:Emerging Technologies”, Proceedings of the Symposium “System Chemistry”,Bozen, Italy, Mai 26-30, 2008, Beilstein Institute), which is herebyincorporated by reference.

A particular example of this reaction under flow conditions is shown inthe reaction scheme below wherein the compound 1b (Z or E/Z 1:1) isconverted to the ester of the formula 4a.

The ester 4a can be produced in this manner with good E/Z ratios, forexample around 80:20.

In yet another particular embodiment of the decarboxylation of compoundsof the formula 1, decarboxylation is carried out in the presence of ametal halide salt MX_(n) (e.g. LiCl) in a polar aprotic solvent, e.g.N-methyl-pyrrolidone (NMP), to yield the corresponding deconjugated acidwith high E/Z ratios.

A particular example of this decarboxylation reaction is shown in thereaction scheme below, in which compound 1c is decarboxylated in thepresence of a salt MX_(n) (e.g. LiCl) in a polar aprotic solvent (e.g.NMP), giving deconjugated acid 6 with high E/Z ratios (e.g. 86:14).

Therefore, the invention provides in another of its aspects, a processfor the preparation of β,γ-unsaturated-γ,γ-disubstituted acids, e.g. theacid 6, said process comprising the step of reacting at a temperature ofbetween about 50 to about 200, more particularly about 75 to about 125degrees centigrade a conjugated malonic acid of the formula 1, e.g. thecompound 1c with a salt MX_(n), optionally in the presence of a polarsolvent, wherein MX_(n) is an inorganic salt or an organic cation/halideanion pair, X is a halide and n is an integer of 1 to 3, and M is agroup I, II or III metal when MX_(n) is an inorganic salt, or M isselected from the group consisting of pyridinium, piperidinium,pyrrolidinium, imidazolium, ammonium, phophonium and sulphonium, whenMX_(n) is an organic cation/halide anion pair. MX_(n) can be an ionicliquid, and in such cases it can act as both salt and a solvent.

The reaction proceeds with good yield and with good E/Z selectivities upto 90:10 or even up to 95:5.

The esters of formula 4, and the acid 6 are both important intermediatesinto the compound 2 and its isomers. Particularly interesting isomers ofcompound 2 can be achieved when the side chain double bonds of ester 4or acid 6 are in the β,γ-position with E configuration.

Methods for a 3-step transformation from an ester of formula 4 to Ambroxvia bicyclic ester 7 are known in the art of fragrance chemistry, e.g.from WO 2006010287, which is hereby incorporated by reference. Anexample of this synthetic route is shown in the scheme below, wherein Ris as hereinabove defined.

The transformation consists of a series of cyclisation and reductionsteps, proceeding with a first cyclisation step, a reduction step, andfinally a second cyclisation step.

The first and second cyclization steps proceed in the presence of anacid, as described more fully in WO2006010287, which is hereinincorporated by reference. Examples of suitable cyclisation agentsinclude mineral acids, organic acids and Lewis acids. Examples ofsuitable mineral acids include phosphoric acid, sulphuric acid andperchloric acids, heteropolyacids such as H₃[P(W₃O₁₀)₄], acid resinssuch as Dowex™ 50 or Amberlyst™. Examples of suitable protonic acidsinclude hydrohalide acids such as hydrogen chloride and hydrogenbromide. Examples of organic acids include acetic acid, trifluoroaceticacid, methanesulphonic acid and chlorosulphonic acid. These named acidsare purely exemplary. It is also possible to use mixtures of theabovementioned acids.

Non-restrictive examples of suitable Lewis acids include products suchas AlCl₃, TiCl₄, SnCl₄ and MeAlCl₂.

The cyclisation steps may be carried out in an inert organic solvent.The selection of a suitable solvent is well known within the skill ofthe art, but suitable examples include petroleum ether, halogenatedhydrocarbons such as chloroform, dichloromethane and trichloroethane,aromatic hydrocarbons such as benzene, toluene and nitrobenzene, etherssuch as diethyl ether, methyl tert-butyl ether and tetrahydrofuran,esters, nitrogen containing hydrocarbons such as nitromethane,nitropropane and acetonitrile.

The reduction step b) may be carried out with a reducing agent. Anyreducing agent that is capable performing the desired transformation maybe used, and the skilled person will readily be able to identify asuitable reducing agent. Non-limiting examples of suitable reducingagents are hydride sources such as lithium aluminium hydride, sodiumborohydride, Red-Al and silanes. The reduction is carried out in aninert solvent, the selection of which will be evident for a skilledperson in the art.

E-Cyclohomofamesic acid 6 is (as is the case with esters 4) anothervaluable precursor of Ambrox 2. The cyclization of 6 to Sclareolide 8and further processing of this key intermediate (8) to Ambrox 2 has beendescribed in numerous articles and patents known to the person skilledin the art, and (as in the case of compounds 4) the double bond of 6should be preferably in the β,γ-position with E-configuration to accessSclareolide 8 and the olfactorily interesting isomers of Ambrox 2 withgood selectivity, for example about 90% or greater.

These transformations can be performed substantially as described abovein relation to esters 4, or according to methods described in EP 525579,EP 5500889, EP 165458 and DE 3240054, all of which citations areincorporated herein by reference.

The compounds 1 can be formed in a quite straightforward fashion by thehydrolysis of the corresponding conjugated malonate 3.

In an example of the synthesis of compounds of the formula 1, compound1a (double bond in the β,γ-position and R=Me) is obtained from compound3a, which is hydrolysed enzymatically using Pig Liver Esterase (PLE) asis shown in the reaction scheme below.

In another example of the synthesis of compounds of the formula 1,compound 1b may be prepared by mono-hydrolysis of conjugated methylmalonate 3a in protic solvents, for example water and alcohols ROH ormixtures of both, with ROH including monoalcohols, diols and triols andR being any organic residue, which may be branched or unbranched, e.g.methyl or ethyl, and in the presence of a base, such as hydroxides ofalkali and/or earth alkali or group III metals. For example conjugatedMeldrum's acid 3b is treated with KOH in methanol (see the reactionscheme below) to give half-malonate 1b:

In yet another example of the synthesis of a compound of the formula 1,compound 1e can be prepared by condensation of aldehyde 5 with malonicacid. This transformation can be carried out with organocatalysts orionic liquids or mixtures of both, used in catalytic or stoichiometricamounts, but catalytic amounts are preferred. The term organocatalyst iswell known in the art. Preferred organocatalysts according to theinvention comprise an amino and an acid function. These functions can belinked covalently in the same molecule, such as in proline and otheramino acids, or such as in glycylglycine (H-Gly-Gly-OH,2-(2-aminoacetamido)acetic acid) and other peptides. The amine componentand the acid component can be mixed before or during the condensationreaction to form an ammonium carboxylate salt. In these salts thecarboxylate is derived from carboxylic or polycarboxylic acids such asacetic acid, malonic acid or citric acid. The amine component is derivedfrom ammonia, a primary, a secondary amine or a polyamine. Secondaryamines are preferred, e.g. piperidine, piperazine, pyrrolidine andmorpholine. The organocatalysts are used in a solvent or solvent systemswhich form azeotropes with water such as cyclohexane, benzene, toluene,iso-propanol or tert-butanol. Azeotropes with boiling points of around70-90° C. are preferred as condensation reactions using such azeotropesproceed and water is removed without uncontrolled decarboxylation ofmalonic acid or condensation product 1c. Under these conditionsrelatively low amounts of 1-1.2 equiv of malonic acid are sufficient forcomplete conversion of aldehyde 5 to acid 1c.

In yet another example of the synthesis of a compound 1, compound 1c canbe prepared by hydrolysis of conjugated malonate 3 with inorganic basein water and in the presence of phase transfer catalysts (PTC) such as18-crown-6 or tetraethylammonium chloride (TEBAC) under reflux.

The starting materials 3a, 3b and 5 are all commonly available reagentsor can be derived from commonly available starting materials accordingto methods well known in the art. A more detailed discussion of thestarting materials and syntheses is set out in the Examples, below.

It has also been found, that it is not necessary to work-up and isolatecompound 1c after condensation of malonic acid with aldehyde 5, becausethe compound 1c can be decarboxylated in-situ to cyclohomofarnesic acid6 giving the same good yield and E/Z ratio as from isolated 1c. Anexample of this in-situ reaction is shown in the reaction scheme below:

Said process represents a significant advantage over previous synthesesof E-Cyclohomofarnesic acid 6, as it allows its efficient one-potpreparation from aldehyde 5 with good yield and purity, using relativelylow amounts of inexpensive catalysts, reagents and solvents, which canbe recycled.

The invention is further described with reference to the followingexamples.

EXAMPLE 1 Dimethyl2-(2-methyl-4-(2,6,6-trimethylcyclohex-1-enyl)butylidene)malonate 3a

Under water-free conditions titanium(IV) chloride (91 g, 0.5 mol) intetrachloromethane (120 ml) are added dropwise within 45 min totetrahydrofuran at 0° C. The mixture is stirred for another 30 min atthis temperature, then2-Methyl-4-(2,6,6-trimethylcyclohex-1-enyl)butanal 5 (50 g, 0.24 mol)(M. Matsui et al., Agric. Biol. Chem. 50, 1475-1480, 1986) and dimethylmalonate (31.7 g, 0.24 mol) in tetrahydrofuran (50 ml) are added within15 min at 0° C. followed by dropwise addition of pyridine (76 g) intetrahydrofuran (240 ml) over 90 min at 0° C. The orange-brownsuspension is stirred for 18 h at 25° C., then poured upon ice/water andextracted with tert-butyl methyl ether. The combined organic layers arewashed with water and conc. NaCl and dried over MgSO₄. After filtrationand evaporation of the solvents the crude product (75 g) isshort-path-distilled giving 62.5 g 3a at 170° C./0.07 mbar (81% yield,purity>98%). Analytical data: ¹H-NMR (400 MHz, CDCl₃): δ 0.95 (s, 6 H),1.1 (d, 3 H), 1.4-1.5 (4H), 1.5-1.6 (2 H), 1.58 (s, 3 H), 1.8-2.0 (2 H),2.5 (m, 1 H), 3.8 (s, 3 H), 3.85 (s, 3 H), 6.85 (d, 1 H) ppm. ¹³C-NMR(400 MHz, CDCl₃): δ 19.45 (t), 19.55 (q), 19.75 (q), 26.4 (t), 28.5 (q),32.7 (t), 34.8 (s), 35.7 (d), 36.8 (t), 39.7 (t), 52.1 (q), 52.2 (q),126.7 (s), 127.1 (s), 136.8 (s), 154.9 (d), 164.4 (s), 166.0 (s). MS(EI): m/z (%) 322 (M⁺, 10), 307 ([M-15]⁺, 2), 275 (6), 259 (7), 243(16), 215 (11), 200 (18), 187 (19), 175 (20), 173 (16), 172 (100), 153(22), 145 (28), 140 (70), 137 (27), 135 (34), 123 (60), 122 (28), 121(42), 109 (35), 108 (34), 95 (62), 93 (36), 81 (44), 79 (33), 55 (36),41 (35). IR (film): 2950 (m), 2926 (m), 2865 (m), 1725 (s), 1642 (w),1454 (w), 1433 (m), 1363 (w), 1327 (w), 1246 (s), 1221 (s), 1204 (s),1168 (w), 1104 (w), 1054 (m), 991 (w), 945 (w), 925 (w), 833 (w), 762(w).

EXAMPLE 22,2-Dimethyl-5-(2-methyl-4-(2,6,6-trimethylcyclohex-1-enyl)butylidene)-1,3-dioxane-4,6-dione3b

Under stirring and nitrogen first L-prolin (0.26 g, 2.2 mmol), then2-Methyl-4-(2,6,6-trimethylcyclohex-1-enyl)butanal 5 (10 g, 45 mmol) (M.Matsui et al., Agric. Biol. Chem. 50, 1475-1480, 1986) are added to2,2-dimethyl-1,3-dioxane-4,6-dione (6.65 g, 45 mmol) in acetonitrile(100 ml) at 25° C. After 90 h at this temperature the solvent isstripped off under reduced pressure. Tert-butyl methyl ether and 2 M HClare added to the residue. Phase separation, extraction of the aqueousphase with tert-butyl methyl ether, washing of the combined organicphase with water, conc. NaHCO₃ and water, drying over MgSO₄, filtrationand evaporation under reduced pressure gives 16 g of an oily residue.Flash chromatography over Silicagel (hexane/tert-butyl methyl ether 9:1)and evaporation of the solvents gives 0.8 g (8%) of aldehyde 5 and 12.8g (87%) of 3b as colorless oils. Analytical data: ¹H-NMR (400 MHz,CDCl₃): δ 0.95 (s, 6 H), 1.15 (d, 3 H), 1.4 (3H), 1.5-1.6 (3 H), 1.55(s, 3 H), 1.75 (s, 6 H), 1.85-1.9 (3 H), 2.05 (m, 1 H), 3.7 (m, 1 H),3.85 (s, 3 H), 7.7 (d, 1 H) ppm. ¹³C-NMR (400 MHz, CDCl₃): δ 19.0 (q),19.4 (t), 19.8 (q), 26.6 (t), 27.6 (2 q), 28.5 (q), 28.6 (q), 32.7 (t),34.8 (s), 35.7 (d), 36.9 (t), 39.7 (t), 104.7 (s), 117.1 (s), 127.6 (s),136.5 (s), 159.8 (s), 162.0 (s), 172.9 (d). MS (DIP, EI): m/z (%) 334(M⁺, 4), 227 (26), 276 (79), 261 (12), 259 (47), 258 (100), 248 (72),243 (81), 233 (28), 230 (21), 220 (26), 215 (34), 202 (41), 189 (31),187 (24), 175 (28), 150 (55), 137 (19), 135 (71), 123 (31), 122 (33),121 (26), 107 (17), 95 (16). IR (film): 2930 (m), 2866 (m), 1736 (s),1624 (m), 1455 (w), 1367 (m), 1276 (s), 1201 (s), 1014 (m), 924 (m), 800(m).

EXAMPLE 3(E)-2-(Methoxycarbonyl)-4-methyl-6-(2,6,6-trimethylcyclohex-1-enyl)hex-3-enoicacid 1a

Conjugated malonate 3a (0.5 g, 1.5 mmol, from a 5% stock solution inmethanol) was incubated with 375 Units Pig Liver Esterase(Sigma-Aldrich) in 100 mM potassium phosphate buffer pH 7.5, at 25° C.and with constant stirring. After 20 h of incubation the pH of thereaction mixture was set to 9 with 30% NaOH followed by incubation atroom temperature for 30 min with constant stirring. The reaction mixturewas then extracted 3 times with 250 ml tert-butyl methyl ether. Theorganic phase was washed twice with 125 ml deionized water and once withsaturated NaCl solution, dried over Na₂SO₄ and finally evaporated underreduced pressure at 45° C. 0.4 g of conjugated malonate 3a wererecovered. The pH of the aqueous phase left from the basic (pH 9)extraction was set to 3 with conc. HCl. Extraction with tert-butylmethyl ether, washing with water and saturated NaCl, drying over Na₂SO₄,filtration and evaporation under reduced pressure at 45° C. gave 62 mg(13%) of deconjugated half malonate 1a as colorless oil and E/Z 72:28according to NMR. The suppression of byproduct 1b depends on the qualityof the PLE employed, with aged PLE (>1 year) giving exclusively isomer1a. Analytical data of the E-isomer: ¹H-NMR (400 MHz, CDCl₃): δ 0.96 (s,6 H), 1.56 (3 H), 1.67 (s, 3 H), 1.4 (2 H), 1.5 (2 H), 1.9 (2 H), 2.0 (4H), 3.6 (s, 3 H, OMe), 4.2 (d, 1 H), 5.4 (d, 1 H) ppm. ¹³C-NMR (400 MHz,CDCl₃): δ 16.4 (q), 19.1 (t), 19.6 (q), 27.2 (t), 28.4 (2q), 32.3 (t),34.6 (s), 39.3 (t), 39.7 (t), 50.9 (d), 52.2 (q), 116.3 (d), 126.8 (s),136.3 (s), 141.0 (s), 169.1 (s), 169.6 (s). Configuration of the E/Zisomers determined by NMR-analysis on a freshly prepared solution of 1ain DMSO-D₆: COSY, HSQC, HMBC and NOESY.

EXAMPLE 42-(Methoxycarbonyl)-4-methyl-6-(2,6,6-trimethylcyclohex-1-enyl)hex-2-enoicacid 1b

Conjugated malonate 3a (10 g, 29.5 mmol) in THF (130 ml) is vigorouslystirred with NaOH (4.8 g, 118 mmol) in water (120 ml) at 25° C. for 5 h.After addition of conc. NaHCO₃ the mixture is extracted with tert-butylmethyl ether. The organic phase, which contains aldehyde 5, isdiscarded. The water phase is acidified with conc. HCl to pH 2 andextracted with tert-butyl methyl ether. The organic phase is dried overMgSO₄, filtered and evaporated under reduced pressure giving 7.5 g (82%)of crude 1b with Z-configuration, which isomerizes upon standing slowlyto an E/Z 1:1 mixture. Analytical data of the Z-isomer: ¹H-NMR (400 MHz,CDCl₃): δ 0.96 (s, 6 H), 1.1 (d, 3 H), 1.4-1.6 (6 H), 1.56 (s, 3 H),1.85-2.0 (4 H), 3.8 (m, 1 H), 3.9 (s, 3 H), 7.2 (d, 1 H) ppm. ¹³C-NMR(400 MHz, CDCl₃): δ 19.41 (t), 19.42 (q), 19.8 (q), 26.4 (t), 28.56 (q),28.57 (q), 32.7 (t), 34.8 (s), 36.0 (d), 36.8 (t), 39.7 (t), 52.6 (t),124.0 (s), 127.3 (s), 136.7 (s), 161.0 (d), 166.6 (s), 167.3 (s).Z-Configuration determined on freshly prepared 1b by non-decoupled¹³C-NMR-(method described in J. Med. Chem. 50, 1322-1334, 2007), HSQC-and HMBC-analysis in DMSO-D₆. MS (DIP, EI): m/z (%) 308 (M⁺, 65), 290(10), 275 (20), 259 (24), 243 (76), 215 (29), 190 (27), 175 (32), 158(100), 140 (43), 123 (29), 121 (22).

EXAMPLE 5

Alternative preparation of conjugated half-malonate 1b: Conjugatedmalonate 3a (10 g, 29 mmol) and KOH (1.9 g, 29 mmol) in dry methanol (60ml) are stirred at 25° C. for 70 h. The mixture is diluted with waterand extracted with tert-butyl methyl ether. The organic phase, whichcontains aldehyde 5, E-ester 4a and substrate 3a (4 g after evaporationof the solvents) is discarded. The aqueous phase is acidified to pH 2and extracted with tert-butyl methyl ether, dried over MgSO₄, filteredand evaporated under reduced pressure to give 6.7 g (76%) of crude 1bwith an E/Z ratio of 1:1 and analytical data identical to the onesobtained for the E/Z mixture in example 4.

EXAMPLE 6

Alternative preparation of conjugated half-malonate 1b from Meldrum'sacid derivative 3b: Compound 3b (10 g, 28.5 mmol) in dry methanol (60ml) containing KOH (1.9 g, 28.5 mmol) is stirred at 65° C. for 4 h.After cooling to 25° C. the mixture is diluted with water and extractedwith tert-butyl methyl ether. The organic phase (1.5 g after evaporationof the solvents) is discarded. The aqueous phase is acidified to pH 2and extracted with tert-butyl methyl ether, dried over MgSO₄, filteredand evaporated under reduced pressure to give 7.6 g (86%) of crude 1b asE/Z 1:1 mixture. The analytical data are identical to the ones obtainedfor the E/Z mixture in example 4.

EXAMPLE 72-(2-Methyl-4-(2,6,6-trimethylcyclohex-1-enyl)butylidene)malonic acid 1c

Dimethyl malonate 3a (10 g, 28 mmol), TEBAC (0.33 g, 1.4 mmol) (or18-Crown 6) and 1N NaOH (120 ml) are stirred at 100° C. for 3 days.Cooled to 25° C. the mixture is extracted with tert-butyl methyl etherand the organic phase, which contains aldehyde 5, is discarded. 100 ml 2N HCl are added to the aqueous phase, which is extracted with tert-butylmethyl ether. The organic phase is washed with water, dried over MgSO₄,filtered and evaporated to give 7.15 g of crude bis-acid 1e (87%).Analytical data: ¹H-NMR (400 MHz, CDCl₃): δ 0.96 (s, 6 H), 1.13 (d, 3H), 1.35-1.6 (6 H), 1.56 (s, 3 H), 1.85-2.1 (4 H), 3.5 (m, 1 H), 7.6 (d,1 H) ppm. ¹³C-NMR (400 MHz, CDCl₃): δ 19.1 (q), 19.4 (t), 19.8 (q), 26.5(t), 28.5 (2q), 32.7 (t), 34.8 (s), 35.6 (d), 36.9 (t), 39.7 (t), 120.0(s), 127.3 (s), 136.8 (s), 168.3 (s), 169.2 (d), 1669.7 (s). MS (DIP,EI): m/z (%) 294 (M⁺, 67), 279 (8), 276 (14), 261 (18), 258 (17), 243(100), 233 (12), 215 (22), 190 (16), 187 (15), 175 (32), 151 (14), 144(44), 135 (32), 126 (14), 123 (31), 121 (16), 107 (9), 95 (9). IR(film): 2969 (m), 2929 (m), 2867 (m), 1701 (s), 1367 (m), 1262 (m), 1237(m), 1199 (s), 1172 (m), 1067 (m), 842 (m), 761 (m).

EXAMPLE 8

Alternative preparation of 1c from aldehyde 5 by condensation withmalonic acid: Aldehyde 5 (50 g, 0.24 mol), malonic acid (31 g, 0.3 mol),and piperidine (1 g, 12 mmol) in 100 ml iso-propanol are heated to 95°C. The iso-propanol/water azeotrope is continuously distilled off at 80°C. and replaced with dry iso-propanol. After 7 h the solvent is strippedoff under reduced pressure. The residue is dissolved in cyclohexane andwashed with 2 M aqueous HCl. The organic phase is concentrated underreduced pressure to give 75 of a viscous residue, which is dissolved inhexane (400 ml), heated to reflux and slowly cooled to 25° C. Theprecipitate is filtered, washed with cold hexane and dried to give 31.5g (45%) of 1c in form of white crystals. Mp 110° C. The analytical dataare identical to the ones obtained for this compound in example 7.

EXAMPLE 9(E)-Methyl4-methyl-6-(2,6,6-trimethylcyclohex-1-enyl)hex-3-enoate 4a

Conjugated malonate 3a (0.5 g, 1.5 mmol), anhydrous lithium chloride (93mg, 2.2 mmol) and water (53 mg, 3 mmol) in N-methyl-pyrrolidone (2.9 g,29 mmol) are heated under stirring to 130° C. After 4 h at thistemperature the mixture is poured upon 2 M HCl and extracted withtert-butyl methyl ether. The combined organic layers are washed withconc. NaHCO₃, conc. NaCl and dried over MgSO₄. After filtration andevaporation of the solvent the crude product (0.64 g) isbulb-to-bulb-distilled to give 0.4 g of 4a at 120° C./0.1 mbar. E/Zratio 82:18. Analytical data of the E-isomer: ¹H-NMR (400 MHz, CDCl₃): δ1.0 (s, 6 H), 1.4 (m, 2 H), 1.55 (m, 2 H), 1.6 (s, 3 H), 1.7 (s, 3 H),1.9 (m, 2 H), 2.1 (4 H), 3.05 (d, 2 H), 3.7 (s, 3 H), 5.35 (t, 1 H) ppm.¹³C-NMR (400 MHz, CDCl₃): δ 16.35 (t), 19.5 (t), 19.8 (q), 27.5 (t),28.6 (q, 2C), 32.8 (t), 33.5 (t), 34.95 (s), 39.8 (t), 40.0 (t), 51.6(q), 115.0 (d), 127.1 (s), 136.9 (s), 139.9 (s), 172.9 (s). MS (EI): m/z(%) 264 (M⁺, 4), 249 ([M-15]⁺, 1), 190 (3), 175 (3), 138 (10), 137(100), 136 (21), 121 (12), 106 (11), 95 (73), 81 (45), 55 (19), 41 (21).Retention times (GC): 9.47 (Z), 9.56 (α,β), 9.62 (E) min. The massspectra of the E- and Z-isomers are identical. IR (film): 2972 (m), 2865(m), 1738 (s), 1434 (m), 1258 (m), 1199 (m), 1148 (m).

EXAMPLE 10

Alternative preparation of E-Cyclohomofarnesyl ester 4a bydecarboxylation of 1b in the GC column: Half-malonate 1b is dissolved at0.1% in tert-butyl methyl ether and is injected. Temperature program:50° C./2 min, 20° C./min→200° C., 35° C./min→270° C. GC/MS: Agilent 5973MSD with HP 6890 Series GC system. Non-polar column: BPX5 from SGE, 5%phenyl 95% dimethylpolysiloxan 0.2 mm×0.25 μm×12 m. Carrier Gas: Helium.Injector temperature: 230° C. Split 1:50. Flow: 1.0 ml/min. Transferline: 250° C. MS-Quadrupol: 106° C. MS-Source: 230° C. Retention times:9.48 (15%, Z-4a), 9.63 (57%, E-4a), 9.87 (12%, α,β-isomer). Themass-spectra of Z-4a and E-4a are identical. The analytical data areidentical to the ones obtained for the EIZ mixture in example 9.

EXAMPLE 11

Alternative preparation of E-Cyclohomofarnesyl ester 4a bydecarboxylation of 1a in DMSO: The NMR-tube containing the solution of1a in DMSO-D₆, as prepared in Example 3 for NMR-analysis, is left at 25°C. as such. Repeated NMR-analysis after 3 days shows completedecarboxylation to 4a (E/Z ratio 78:22). The other analytical data areidentical with the ones obtained for the E/Z mixture from example 9.

EXAMPLE 12

(E)-4-methyl-6-(2,6,6-trimethylcyclohex-1-enyl)hex-3-enoic acid 6:decarboxylation of 1c in the presence of LiCl.

Conjugated malonic acid 1c (2 g, 6.7 mmol) and anhydrous lithiumchloride (0.3 g, 6.7 mmol) in N-methyl-pyrrolidone (4.5 g, 45 mmol) areheated under stirring to 100° C. After 2 h at this temperature themixture is poured at 25° C. upon 2 M HCl and extracted with tert-butylmethyl ether. The combined organic layers are washed with water, conc.NaHCO₃ and conc. NaCl and dried over MgSO₄. Filtration and evaporationof the solvent under vacuum gives 1.9 g of crude 6 (quant). E/Z ratio86:14 (¹³C-NMR). The analytical data of 6 are identical to the onesdescribed for this compound in EP 550889 (Kuraray, 1991).

EXAMPLE 13

Conjugated malonic acid 1c (3 g, 10 mmol) and1-ethyl-3-methylimidazolium chloride (EMIMCl) (1.5 g, 10 mmol) inN-methyl-pyrrolidone (6.6 g, 66 mmol) are heated under stirring andnitrogen to 100° C. After 5 h at this temperature the mixture is pouredat 25° C. upon 2 M HCl and extracted with tert-butyl methyl ether. Thecombined organic layers are washed with 2 M HCl, water and conc. NaHCO₃and are dried over MgSO₄. Filtration and evaporation of the solventunder vacuum gives 2.6 g of crude 6 (quant). E/Z ratio 83:17 (¹³C-NMR).The analytical data of 6 are identical to the ones described for thiscompound in EP 550889 (Kuraray, 1991).

EXAMPLE 14 One-Pot-Preparation of Acid 6 from Aldehyde 5 Catalyzed byAmmonium Acetate

Under stirring and nitrogen aldehyde 5 (104 g, 0.5 mol), ammoniumacetate (3.85 g, 50 mmol) and malonic acid (62.4 g, 0.6 mol) are heatedin cyclohexane (250 ml) and tert-butanol (25 ml) to reflux (78° C.).After 2 h 5.5 ml water are collected in the Dean-Stark trap and after 4h complete conversion is checked by TLC (system as above). 210 mlcyclohexane are distilled under reduced pressure (350 mbar). Magnesiumchloride (24 g) in N-methyl-pyrrolidine (100 ml) are added within 5 min.After 5 h at 75° C. complete conversion of intermediate 1c to monoacid 6is detected by TLC (system as above). The reaction mixture is cooled to25° C. and poured upon water (400 ml). Extraction with hexane, washingof the combined organic layers with water, drying over MgSO4, filtrationand evaportion of the combined organic phases under reduced pressuregives 123 g of an oily residue residue, which slowly solidifies uponstanding. Purity=61% (E), according to ¹H-NMR with internal standarddioxane. Yield: 56% based on aldehyde 5 and corrected by purity. RatioE/Z/conj=85:8:7 (¹³ C-NMR in CDCl₃). The other analytical data of acid 6obtained by this method are identical with the ones obtained for thiscompound (examples 12, 15, 16 and literature).

EXAMPLE 15 One-Pot-Preparation of Acid 6 from Aldehyde 5 Catalyzed byProline

Under stirring and nitrogen aldehyde 5 (50 g, 0.24 mol), L-proline (2.8g, 24 mmol) and malonic acid (31 g, 0.3 mol) are heated in cyclohexane(60 ml) and tert-butanol (40 ml) to reflux (80-85° C.). Thecyclohexane/tert-butanol/water azeotropes are continuously distilled offand replaced with dry cyclohexane/tert-butanol. After 3 h completeconversion to bisacid 1c is detected by TLC. 60 ml ofcyclohexane/tert-butanol/water azeotrope are distilled off at 80-85° C.Water-free Magnesium chloride (11.5 g, 0.12 mol) in dryN-methyl-pyrrolidinone (157 g, 1.55 mol) is added and the mixture heatedfor another 3 hours at 80-85° C. The solution is cooled to 25° C. andpoured upon 2N aqueous HCl. Extraction with cyclohexane, washing of theorganic phase with aqueous 2N HCl, extraction of the combined aqueouslayers with cyclohexane and evaportion of the combined organic phasesunder reduced pressure gives a residue, which is further dried withcyclohexane under reduced pressure giving 63 g of a yellow oil with apurity of 79.5% (E+Z, determined by ¹H-NMR with internal standarddioxane). E/Z ratio: 90:10 (according to ¹³C-NMR). The crude product isdissolved in hexane and slowly cooled to −20° C. The precipitate isfiltered, washed with cold hexane to give 39.5 g of pure E-acid 6 (66%from aldehyde 5). Purity=96%, according to ¹H-NMR with internal standarddioxane. Mp=49° C. The other analytical data of acid 6 obtained by thismethod are identical with the ones obtained for this compound (examples12, 14, 16 and literature).

EXAMPLE 16 One-Pot-Preparation of Acid 6 from Aldehyde 5 Catalyzed byGlycinyl Glycine

Prepared as described in example 14 from aldehyde 5 (50 g, 0.24 mol),H-Gly-Gly-OH (3.2 g, 24 mmol), malonic acid (31 g, 0.3 mol), magnesiumchloride (11.5 g, 0.12 mol) in dry N-methyl-pyrrolidinone (71 g, 0.71mol) using the same amount of solvents cyclohexane and t-Butanol within3 h (for condensation) and 4 h (for decarboxylation). Work-up gave 70 gof crude 6 with a purity of 70% (E+Z, determined by ¹H-NMR with internalstandard dioxane). EIZ ratio: 90:10 (according to ¹³C-NMR). Yield: 74%(corrected and based on the E-isomer). The other analytical data of acid6 obtained by this method are identical with the ones obtained for thiscompound (examples 12, 14, 15 and literature).

The invention claimed is:
 1. A compound of formula 1

wherein R is aryl or substituted aryl.
 2. A compound of formula 1

wherein R is hydrogen.